One of the most severe disorders of oral-motor function is tardive dyskinesia (TD). an iatrogenic syndrome which develops following the chronic administration of antipsychotic medication (neuroleptics). Treatment of TD and an understanding of the biological basis of the disorder remain unclear. Research directed at understanding the neurochemical processes involved in TD would enhance effective management of the disorder, assist in the development of safer neuroleptics, and provide information concerning the basic neural mechanisms involved in extrapyramidal control of oral-motor function. The series of studies proposed here will utilize a unique computerized method of analyzing orofacial activity in rats. This system provides detailed measures of the number and form of oral movements and has led to the development of a novel animal model of TD in which rats exhibit neuroleptic-induced oral dyskinesias similar in many respects to the human condition. Based on this rodent model, the present project will investigate the pharmacology of oral movements following both systemic and intracranial administration of a variety of drugs. Since most evidence suggests that neurochemical alterations in the basal ganglia underlie the orofacial dyskinesias of TD, these studies will focus on neurotransmitters known to mediate basal ganglia function, including dopamine, GABA, and acetylcholine, as well as the neuropeptides cholecystokinin and neurotensin. Following initial acute drug studies, appropriate drugs will then be used as pharmacological probes in rats exhibiting neuroleptic- induced oral dyskinesias. Other experiments will involve the use of in vivo microdialysis as a means of assessing dynamic changes in brain neurochemistry that occur in basal ganglia regions mediating orofacial movements. This approach will focus particularly on alterations in dopaminergic neurotransmission in chronic neuroleptictreated animals. These experiments address both the fundamental neuropharmacology of oral motor behaviors as well as neurochemical processes involved in pathological oral activity caused by neuroleptic treatment. The questions addressed in this proposal can only be answered by utilizing an animal model such as that proposed here.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Neurological Sciences Subcommittee 1 (NLS)
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Washington State University
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Grimm, J W; See, R E (2000) Chronic haloperidol-induced alterations in pallidal GABA and striatal D(1)-mediated dopamine turnover as measured by dual probe microdialysis in rats. Neuroscience 100:507-14
Grimm, J W; Kruzich, P J; See, R E (1998) Emergence of oral and locomotor activity in chronic haloperidol-treated rats following cortical N-methyl-D-aspartate stimulation. Pharmacol Biochem Behav 60:167-73
Grimm, J W; Aravagiri, M; See, R E (1998) Ovariectomy results in lower plasma haloperidol levels in rats following chronic administration. Pharm Res 15:1640-2
See, R E; Lynch, A M; Sorg, B A (1996) Subchronic administration of clozapine, but not haloperidol or metoclopramide, decreases dopamine D2 receptor messenger RNA levels in the nucleus accumbens and caudate-putamen in rats. Neuroscience 72:99-104
See, R E; Lynch, A M (1996) Duration-dependent increase in striatal glutamate following prolonged fluphenazine administration in rats. Eur J Pharmacol 308:279-82
Chapman, M A; See, R E (1996) Differential effects of unique profile antipsychotic drugs on extracellular amino acids in the ventral pallidum and globus pallidus of rats. J Pharmacol Exp Ther 277:1586-94
Chapman, M A; See, R E (1996) The neurotensin receptor antagonist SR 48692 decreases extracellular striatal GABA in rats. Brain Res 729:124-6
See, R E; Lynch, A M (1995) Chronic haloperidol potentiates stimulated glutamate release in caudate putamen, but not prefrontal cortex. Neuroreport 6:1795-8
See, R E; Lynch, A M; Aravagiri, M et al. (1995) Chronic haloperidol-induced changes in regional dopamine release and metabolism and neurotensin content in rats. Brain Res 704:202-9
Meil, W; See, R E (1994) Single preexposure to fluphenazine produces persisting behavioral sensitization accompanied by tolerance to fluphenazine-induced striatal dopamine overflow in rats. Pharmacol Biochem Behav 48:605-12

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